Poly(ketals) and related compositions and methods

Abstract

Compositions comprising polymers comprising one or more ketal, monothioketal, and/or thioketal bonds are provided, as well as related methods and kits. In some embodiments, a polymer may comprise one or more repeat units comprising one or more ketal, monothioketal, and/or thioketal bonds and a precursor of a pharmaceutically active agent. The precursor of the pharmaceutically active agent may be located in the backbone or may be a pendant group. The polymer may degrade in certain environments (e.g., aqueous environments, acidic environments, in vivo, etc.) to produce the pharmaceutically active agent and other biocompatible degradation products, such as certain ketones, alcohols, and/or thiols. Regardless of the location of the precursor of the pharmaceutically active agent in the repeat unit(s), the polymer may have a prolonged degradation time and/or release of the pharmaceutically active agent in certain environments. Various compositions, described herein, may be particularly well suited for applications requiring extended release of pharmaceutically active agents, such as the treatment of ophthalmic disorders.

The invention claimed is: 
     
       1. A composition, comprising a polymer comprising one or more repeat units of formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 each R 1  and R 2  is independently alkyl, optionally substituted; 
 each Z is independently a precursor of a pharmaceutically active agent; 
 each X is independently -L 1 -(R 3 ) q -L 1 -, wherein each R 3  is optionally substituted with 0-5 T 1 ; 
 each M is independently -L 2 -(R 4 ) r -L 2 -, wherein each R 4  is optionally substituted with 0-5 T 2 ; 
 each R 3  and R 4  is independently alkylene, heteroalkylene, carbocyclylene, heterocyclylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, or heteroarylene; 
 each L 1  and L 2  is independently —O— or —S—, wherein at least one of L 1  or L 2  is —S—; 
 each T 1  and T 2  is independently R 5  or —R 6 —Z 2    
 each R 5  is alkyl, heteroalkyl, alkenyl, heteroalkenyl, heterocyclyl, hydroxyl, halo, thio, oxo, thioxo, amino, —NO 2 , or acyl, optionally substituted; 
 each R 6  is alkylene, heteroalkylene, alkenylene, heteroalkenylene, —O—, —S—, —N(R)—, or acylene, optionally substituted; 
 Z 2  is a pendant precursor of a pharmaceutically active agent; 
 R is independently hydrogen or alkyl; 
 n is 1-5; 
 m is 0-5; and 
 q and r are independently 1-5; 
 
       provided that: 
       (i) the pharmaceutically active agent comprises two or more hydroxyl groups; 
       (ii) the pharmaceutically active agent is a steroid, prostaglandin, prostaglandin analog, or a prostamide; 
       (iii) the pharmaceutically active agent is an anti-glaucoma agent; 
       (iv) at least one of X, Z, or M comprises —S—; or 
       (v) m is greater than or equal to 1. 
     
     
       2. The composition of  claim 1 , wherein the steroid is selected from the group consisting of estradiol, dexamethasone, prednisone, testosterone, cholic acid, triamcinolone acetonide, triamcinolone, lanosterol, cortisol, and nandrolone. 
     
     
       3. The composition of  claim 1 , comprising particles comprising the polymer, wherein the largest cross-sectional dimension of the particles is less than or equal to about 1000 microns. 
     
     
       4. The composition of  claim 1 , wherein Z has the structure:
   -T-Z 1 -T-, 
 
       wherein:
 Z is a portion of the pharmaceutically active agent; 
 T is -L 3 - or -L 3 -(R 7 ) t —; 
 L 3  is —O— or —S—; 
 R 7  is alkylene, heteroalkylene, alkenylene, heteroalkenylene, —O—, —S—, —N(R)—, or acylene, optionally substituted; and 
 each t is independently 0-5. 
 
     
     
       5. The composition of  claim 1 , wherein:
 each R 1  and R 2  is independently C 1-2  alkyl; 
 each X is independently -L 1 -(R 3 ) q -L 1 -, wherein each R 3  is optionally substituted with 0-3 T 1 ; 
 each M is independently -L 2 -(R 4 ) r -L 2 -, wherein each R 4  is optionally substituted with 0-3 T 2 ; 
 each R 3  and R 4  is independently alkylene, heteroalkylene, carbocyclylene, heterocyclylene, heteroalkenylene, arylene, or heteroarylene; 
 R is independently hydrogen; 
 n is 1 or 2 and m is 0-2; and 
 q and r are independently 1-3. 
 
     
     
       6. The composition of  claim 1 , wherein at least one of L 1  or L 2  is —O—. 
     
     
       7. A pharmaceutical composition comprising:
 a therapeutically effective amount of the composition of  claim 1 ; and 
 one or more pharmaceutically acceptable excipients. 
 
     
     
       8. A method of treating an ophthalmic disorder in a patient, comprising:
 administering the pharmaceutical composition of  claim 7  to the patient. 
 
     
     
       9. A kit comprising:
 a pharmaceutical composition as in  claim 7 ; and 
 instructions for use of the composition in a subject. 
 
     
     
       10. An in vitro method of administering a composition to a cell, comprising:
 administering the composition of  claim 1  to a cell. 
 
     
     
       11. The composition of  claim 1 , wherein each Z is independently a precursor of an anti-glaucoma agent. 
     
     
       12. The composition of  claim 11 , wherein the anti-glaucoma agent is selected from the group consisting of prostaglandin analogs, beta blockers, alpha agonists, and carbonic anhydrase inhibitors. 
     
     
       13. The composition of  claim 11 , wherein the anti-glaucoma agent is selected from the group consisting of tafluprost, bimatoprost, travopost, latanoprost, timolol, unoprostone, tafluprost acid, latanoprost acid, and bimatoprost acid. 
     
     
       14. The composition of  claim 11 , wherein the anti-glaucoma agent is tafluprost.